Intensive Care Med (2003) 29:646–651 DOI 10.1007/s00134-003-1666-6
Axel Nierhaus Barbara Montag Nicole Timmler Daniel P. Frings Kai Gutensohn Roman Jung Claus G. Schneider Werner Pothmann Anne K. Brassel Jochen Schulte am Esch
Received: 5 August 2002 Accepted: 10 January 2003 Published online: 21 February 2003 © Springer-Verlag 2003 Financial support came from institutional funds of the Department of Anaesthesiology, University Hospital Eppendorf, Hamburg, Germany.
A. Nierhaus (✉) · B. Montag N. Timmler · D. P. Frings · W. Pothmann A. K. Brassel · J. Schulte am Esch Department of Anaesthesiology, University Hospital Eppendorf, 20246 Hamburg, Germany e-mail:
[email protected] Tel.: +49-40-428032450 Fax: +49-40-428035372 K. Gutensohn Department of Transfusion Medicine, University Hospital Eppendorf, 20246 Hamburg, Germany R. Jung Department of Clinical Chemistry, University Hospital Eppendorf, 20246 Hamburg, Germany C. G. Schneider Department of General Surgery, University Hospital Eppendorf, 20246 Hamburg, Germany
B R I E F R E P O RT
Reversal of immunoparalysis by recombinant human granulocyte-macrophage colony-stimulating factor in patients with severe sepsis
Abstract Objective: To evaluate the effect of recombinant human granulocyte-macrophage colony-stimulating factor (rhGM-CSF) on immunoparalysis as defined by a sustained decrease of HLA-DR expression on monocytes in patients with severe sepsis. Design: Prospective, nonrandomised observational study. Setting: Two anaesthesiological intensive care units of a university hospital. Intervention: Administration of a daily dose of 5 µg/kg rhGM-CSF over a period of 3 days. Patients: Nine consecutive patients with severe sepsis and a documented HLA-DR expression on peripheral monocytes of less than 150 mean fluorescence intensity (MFI) over a period of at least 48 h prior to intervention. Measurements and results: Mean MFI was 69.4±13.2 24 h before and 56.7±8.2 on the day of the administration of 5 µg/kg rhGM-CSF. Within 24 h a significant increase of HLA-DR expression to a mean of 327.7±78.8 MFI was observed in all patients. This increase was maintained on days 2–10. It was accompanied by a significant rise in white
Introduction The antigen-presenting HLA-DR receptor complex of monocytes is of vital importance for a fully functional innate immune response upon contact with pathogens [1]. In severely diseased patients, a downregulation of the expression of HLA-DR receptors on monocytes and
blood count. The ex vivo TNF-α production in whole blood after lipopolysaccharide (LPS)-stimulation increased significantly from a mean of 82±29.2 pg/ml to 793±546.8 pg/ml. Apart from febrile reactions in two patients, no side effects were recorded. No increases of pro-inflammatory markers (IL-6, C-reactive protein, LPS-binding protein, procalcitonin) were observed. SOFA values before and after rhGM-CSF did not differ significantly. The mortality rate was 33%. Conclusion: This preliminary study demonstrates that rhGM-CSF upregulates HLA-DR expression on monocytes in septic patients with multi-organ dysfunction. Moreover, with the concomitant increase of the ex vivo whole blood TNF-α response, this upregulation of a monocytic activation marker is paralleled by a functional recovery. Keywords Innate immune response · HLA-DR · Monocytes · Granulocyte-macrophage colony-stimulating factor (GM-CSF) · Sepsis · Intensive care
of their ex vivo cytokine production following lipopolysaccharide (LPS) stimuli can be observed [2, 3]. Monocyte deactivation during systemic inflammatory response syndrome (SIRS), sepsis and septic shock has been shown to be associated with increased morbidity and an unfavourable outcome [4, 5]. In previous ex vivo studies [6, 7, 8] rhGM-CSF had been demonstrated to be capa-
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ble of restoring monocyte responsiveness and of counteracting the immunodepressive effects of anti-inflammatory mediators like interleukin (IL)-10. Recently, in patients with adult respiratory distress syndrome and severe sepsis, GM-CSF was shown to ameliorate respiratory dysfunction overall, and to increase blood granulocyte superoxide production and phagocytic function without relevant side effects [9]. Endogenous GM-CSF is an 18–30 kDa glycosylated protein which stimulates haematopoiesis in the bone marrow and causes an increase of the neutrophil and eosinophil count [10]. GM-CSF also enhances the inflammatory response of mature macrophages and monocytes [11]. In Europe, an rhGM-CSF (14.4 kDa, non-glycosylated, E. coli-derived; Molgramostim) is approved for the treatment of chemotherapy-induced neutropenia and for bone marrow allograft recipients. RhGM-CSF has been shown to be of little toxicity in haematological patients. There is no evidence that GM-CSF causes malignant transformation of the target cells or deteriorates the course of leukaemia [12]. The most frequently reported side effects are fever and a flu-like syndrome. In this preliminary study, for the first time we have assessed the effect of GM-CSF on sepsis-induced HLA-DR depression in nine severely ill adult patients.
Materials and methods Patients and intervention After approval from the local ethics committee and after obtaining informed consent from the legal substitute (next of kin in all cases), nine patients with severe sepsis (ACCP/SCCM criteria) and with a sustained depression of HLA-DR on monocytes (
